Research Article| Volume 141, 155397, April 2023

Activins, follistatins and inhibins in postmenopausal osteoporosis: A proof of concept, case-control study

Published:December 29, 2022DOI:


      • Components of the Activins - Follistatins axis follow an opposite pattern of correlations for age and BMI vs. BMD
      • Follistatin (but not FSTL 3) and its ratios with activins are inversely associated with lumbar spine BMD
      • Follistatin (but not FSTL 3) and its ratios with activins are inversely associated with the presence of osteoporosis
      • Inhibin B levels were lower in postmenopausal osteoporotic women



      Bone metabolism has been proposed to be affected by the activins-follistatins-inhibins (AFI) hormonal system. We aimed to evaluate AFI in patients with osteoporosis and osteopenia compared with postmenopausal and premenopausal controls.


      In this case-control study, circulating levels of the AFI system were evaluated, individually and jointly, between postmenopausal women with osteoporosis (BMD T-score ≤−2.5; n = 25) or osteopenia (BMD T-score >−2.5 and ≤−1; n = 25) and postmenopausal women with normal BMD (T-score >−1.0; n = 25) or premenopausal women with normal BMD (Z-score >−1.0; n = 25), with and without adjustment for potential confounders.


      In the sum of participants, AFI molecules and their ratios followed an opposite pattern of correlations for age and BMI vs. BMD. In unadjusted models, FSTL3 concentrations were higher, whereas activin B, inhibin A and inhibin B and the ratios of activin B/follistatin and activin B/FSTL3 were lower in the three postmenopausal groups compared with the premenopausal group. Activin A/follistatin and activin AB/follistatin ratios were lower in the osteoporosis group than the other three groups. After adjustment for BMI and age, inhibin B (p = 0.005), and the ratios of activin A/follistatin (p = 0.009), activin B/follistatin (p = 0.040) and activin AB/follistatin (p = 0.003) were lower in the osteoporotic group compared with the other groups. In fully adjusted logistic regression analysis log(inhibin B) (p = 0.041), log(activinA/follistatin) (p = 0.014), log(activinB/follistatin) (p = 0.025) and log(activinAB/follistatin) (p = 0.021), but not FSTL3, remained independently associated with the presence of osteoporosis.


      Lower inhibin B and higher ratios of activins A, B, and AB to follistatin are associated with lumbar spine BMD and the presence of osteoporosis independently from age or BMI.

      Graphical abstract


      ActRIIA (activin receptor type IIA), AFI (activins-follistatins-inhibins system), BMD (bone mineral density), BMI (body mass index), FN (femoral neck), FSH (follicle-stimulating hormone), FSTL3 (follistatin-like 3), LS (lumbar spine), TGF-β (transforming growth factor-β)


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        • Bowser M.
        • Herberg S.
        • Arounleut P.
        • Shi X.
        • Fulzele S.
        • Hill W.D.
        • et al.
        Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells.
        Exp Gerontol. 2013; 48: 290-297
        • Vale W.
        • Wiater E.
        • Gray P.
        • Harrison C.
        • Bilezikjian L.
        • Choe S.
        Activins and inhibins and their signaling.
        Ann N Y Acad Sci. 2004; 1038: 142-147
        • Lotinun S.
        • Pearsall R.S.
        • Horne W.C.
        • Baron R.
        Activin receptor signaling: a potential therapeutic target for osteoporosis.
        Curr Mol Pharmacol. 2012; 5: 195-204
        • Anastasilakis A.D.
        • Polyzos S.A.
        • Makras P.
        • Gkiomisi A.
        • Savvides M.
        • Papatheodorou A.
        • et al.
        Circulating activin-a is elevated in postmenopausal women with low bone mass: the three-month effect of zoledronic acid treatment.
        Osteoporos Int. 2013; 24: 2127-2132
        • Gilson H.
        • Schakman O.
        • Kalista S.
        • Lause P.
        • Tsuchida K.
        • Thissen J.P.
        Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin.
        Am J Physiol Endocrinol Metab. 2009; 297: E157-E164
        • Anastasilakis A.D.
        • Polyzos S.A.
        • Skouvaklidou E.C.
        • Kynigopoulos G.
        • Saridakis Z.G.
        • Apostolou A.
        • et al.
        Circulating follistatin displays a day-night rhythm and is associated with muscle mass and circulating leptin levels in healthy, young humans.
        Metabolism. 2016; 65: 1459-1465
        • Liu Y.
        • Lehar A.
        • Rydzik R.
        • Chandok H.
        • Lee Y.S.
        • Youngstrom D.W.
        • et al.
        Local versus systemic control of bone and skeletal muscle mass by components of the transforming growth factor-beta signaling pathway.
        Proc Natl Acad Sci U S A. 2021; 118
        • Fahmy-Garcia S.
        • Farrell E.
        • Witte-Bouma J.
        • Robbesom-van den Berge I.
        • Suarez M.
        • Mumcuoglu D.
        • et al.
        Follistatin effects in migration, vascularization, and osteogenesis in vitro and bone repair in vivo.
        Front BioengBiotechnol. 2019; 7: 38
        • Gaddy-Kurten D.
        • Coker J.K.
        • Abe E.
        • Jilka R.L.
        • Manolagas S.C.
        Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures.
        Endocrinology. 2002; 143: 74-83
        • Gaddy D.
        Inhibin and the regulation of bone mass.
        Curr Osteoporos Rep. 2008; 6: 51-56
        • Perrien D.S.
        • Achenbach S.J.
        • Bledsoe S.E.
        • Walser B.
        • Suva L.J.
        • Khosla S.
        • et al.
        Bone turnover across the menopause transition: correlations with inhibins and follicle-stimulating hormone.
        J Clin Endocrinol Metab. 2006; 91: 1848-1854
        • Vural F.
        • Vural B.
        • Yucesoy I.
        • Badur S.
        Ovarian aging and bone metabolism in menstruating women aged 35–50 years.
        Maturitas. 2005; 52: 147-153
        • Lodberg A.
        • van der Eerden B.C.J.
        • Boers-Sijmons B.
        • Thomsen J.S.
        • Bruel A.
        • van Leeuwen J.
        • et al.
        A follistatin-based molecule increases muscle and bone mass without affecting the red blood cell count in mice.
        FASEB J. 2019; 33: 6001-6010
        • Suh J.
        • Kim N.K.
        • Lee S.H.
        • Eom J.H.
        • Lee Y.
        • Park J.C.
        • et al.
        GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone.
        Proc Natl Acad Sci U S A. 2020; 117: 4910-4920
        • Vamvini M.T.
        • Aronis K.N.
        • Chamberland J.P.
        • Mantzoros C.S.
        Energy deprivation alters in a leptin- and cortisol-independent manner circulating levels of activin a and follistatin but not myostatin in healthy males.
        J Clin Endocrinol Metab. 2011; 96: 3416-3423
        • Moragianni V.A.
        • Aronis K.N.
        • Chamberland J.P.
        • Mantzoros C.S.
        Short-term energy deprivation alters activin a and follistatin but not inhibin B levels of lean healthy women in a leptin-independent manner.
        J Clin Endocrinol Metab. 2011; 96: 3750-3758
        • Perakakis N.
        • Upadhyay J.
        • Ghaly W.
        • Chen J.
        • Chrysafi P.
        • Anastasilakis A.D.
        • et al.
        Regulation of the activins-follistatins-inhibins axis by energy status: impact on reproductive function.
        Metabolism. 2018; 85: 240-249
        • Brinkoetter M.
        • Magkos F.
        • Vamvini M.
        • Mantzoros C.S.
        Leptin treatment reduces body fat but does not affect lean body mass or the myostatin-follistatin-activin axis in lean hypoleptinemic women.
        Am J Physiol Endocrinol Metab. 2011; 301: E99-E104
        • Bouzoni E.
        • Perakakis N.
        • Mantzoros C.S.
        Circulating profile of activin-follistatin-inhibin Axis in women with hypothalamic amenorrhea in response to leptin treatment.
        Metabolism. 2020; 113154392
        • Tsompanidis A.
        • Vafiadaki E.
        • Bluher S.
        • Kalozoumi G.
        • Sanoudou D.
        • Mantzoros C.S.
        Ciliary neurotrophic factor upregulates follistatin and Pak1, causes overexpression of muscle differentiation related genes and downregulation of established atrophy mediators in skeletal muscle.
        Metabolism. 2016; 65: 915-925
        • Sienkiewicz E.
        • Magkos F.
        • Aronis K.N.
        • Brinkoetter M.
        • Chamberland J.P.
        • Chou S.
        • et al.
        Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women.
        Metabolism. 2011; 60: 1211-1221
        • Audi L.
        • Mantzoros C.S.
        • Vidal-Puig A.
        • Vargas D.
        • Gussinye M.
        • Carrascosa A.
        Leptin in relation to resumption of menses in women with anorexia nervosa.
        Mol Psychiatry. 1998; 3: 544-547
        • Bluher S.
        • Mantzoros C.S.
        The role of leptin in regulating neuroendocrine function in humans.
        J Nutr. 2004; 134: 2469S-2474S
        • Chantry A.D.
        • Heath D.
        • Mulivor A.W.
        • Pearsall S.
        • Baud'huin M.
        • Coulton L.
        • et al.
        Inhibiting activin-a signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo.
        J Bone Miner Res. 2010; 25: 2633-2646
        • Lodberg A.
        • Eijken M.
        • van der Eerden B.C.J.
        • Okkels M.W.
        • Thomsen J.S.
        • Bruel A.
        A soluble activin type IIA receptor mitigates the loss of femoral neck bone strength and cancellous bone mass in a mouse model of disuse osteopenia.
        Bone. 2018; 110: 326-334
        • Lotinun S.
        • Pearsall R.S.
        • Davies M.V.
        • Marvell T.H.
        • Monnell T.E.
        • Ucran J.
        • et al.
        A soluble activin receptor type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in cynomolgus monkeys.
        Bone. 2010; 46: 1082-1088
        • Fajardo R.J.
        • Manoharan R.K.
        • Pearsall R.S.
        • Davies M.V.
        • Marvell T.
        • Monnell T.E.
        • et al.
        Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis).
        Bone. 2010; 46: 64-71
        • Ruckle J.
        • Jacobs M.
        • Kramer W.
        • Pearsall A.E.
        • Kumar R.
        • Underwood K.W.
        • et al.
        Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women.
        J Bone Miner Res. 2009; 24: 744-752